Post-traumatic Stress Disorder (PTSD) is hypothesized to involve disruption of fear extinction processes, perhaps specifically the loss of extinction learning and habituation. Fear extinction is the gradual loss of learned fear responses to conditioned fear stimuli (CS) when the CS is no longer predictive of the noxious or fearful events. Fear extinction requires glutamatergic neurotransmission in the amygdala, and is facilitated by glutamate agonists in both humans and animals. PTSD patients exhibit high levels of corticotropin-releasing factor (CRF) in cerebrospinal fluid. CRF is a neuropeptide that controls behavioral, endocrine, and autonomic responses to stress by activating two known high-affinity CRF receptors: CRF-R1 and CRF-R2. Since CRF concentrations in cerebrospinal fluid are positively associated with the severity of PTSD symptoms, CRF deregulation may be an important pathophysiological substrate for PTSD. Given recent in vitro data indicating that CRF receptors modulate glutamatergic transmission in the amygdala, this R21 application will test a novel model of mechanisms underlying fear extinction deficits in PTSD. The model predicts that the excessive CRF release observed in PTSD patients may disrupt fear extinction via chronic CRF-R1 activation in the amygdala. Hence, the proposed studies in this R21 application will test the hypothesis that acute and chronic CRF receptor activation modulates fear extinction learning. Specific predictions are that: [1] CRF-R1 activation, which reduces glutamatergic transmission in the amygdala, will disrupt fear extinction learning; and [2] CRF-R2 activation, which increases glutamatergic transmission in the amygdala, will enhance fear extinction learning. Aim 1 of this project will use selective CRF-R1 and CRF-R2 ligands during extinction training of fear potentiated startle in normal mice to explore the potentially important and differential influences of CRF receptor subtypes on extinction learning. Aim 2 of this R21 application will explore the validity of mutant mice with CRF-over-expression specifically limited to the central nervous system as a new model with both face and construct validity for PTSD. This aim will test the hypothesis that chronic CRF elevations in CRF-over-expressing mice disrupt fear extinction via the activation of the CRF-R1 receptor. The results of these studies could lead to a new line of investigation involving an innovative combination of pharmacological and experience-based treatments using CRF-R1 antagonists to treat PTSD. [unreadable] [unreadable] [unreadable]